Kits for local delivery of water soluble agents and methods of use

ABSTRACT

A kit includes a mesh substrate and a polymer that is fixed to the mesh substrate. The polymer includes an active agent that is configured to elute over time. The kit further includes a hemostatic agent. The hemostatic agent is separate from the mesh substrate and the polymer. Systems and methods are disclosed.

TECHNICAL FIELD

The present disclosure generally relates to kits and methods configuredfor anchoring an implantable medical device within a body, and moreparticularly to a kit that includes an anchorage device and at least onehemostatic agent that is separate from the anchorage device and methodsof using the kit.

BACKGROUND

Some known anchorage devices may be used to secure an implantablemedical device within a body of a patient. The anchorage device andimplantable medical device can be inserted into a desired locationwithin the body of the patient. The anchorage device can be used to helpanchor or support the implantable medical device with surroundingtissue. Some known anchorage devices are used to provide temporarysupport to tissue during a healing process. For example, some knownanchorage devices can secure one portion of tissue to another portion oftissue.

Pocket hematoma is a frequent complication following deviceimplantation. For example, it is estimated that hematomas account forabout 15 to 20% early intervention after pacemaker or ImplantableCardioverter Defibrillator (ICD) implantations. The development of aclinically significant pocket hematoma increases the risk of aninfection by a factor or 7.7×. While increased use of anticoagulanttherapy has been assigned as a possible cause, its use cannot be totallydiscounted due to the danger of thromboembolic events, includingcerebral stroke. Hematomas may increase pain, require re-interventionfor draining, and delay healing. There is an unmet clinical need toaddress postoperative bleeding in the pectoral pocket related to CardiacImplantable Electronic Device (CIED) procedures in order to reduce theincidence of hematoma. Some anchorage devices include a hemostatic agentincorporated into the anchorage device to stop or reduce the flow ofblood at a surgical site and/or speed up the blood clotting processwhile anchoring the implantable medical device to tissue. See, forexample, U.S. patent application Ser. No. 15/582,935 filed on May 1,2017, U.S. patent application Ser. No. 15/583,025, filed on May 1, 2017,U.S. patent application Ser. No. 15/583,086, filed on May 1, 2017, U.S.patent application Ser. No. 15/583,124, filed on May 1, 2017, and U.S.patent application Ser. No. 15/583,153, filed on May 1, 2017, which areeach owned by Applicant and expressly incorporated by reference herein,in their entireties. However, the type of hemostatic agent and theamount of hemostatic agent that is directed to a target area can varydue to factors, such as, for example, the type of implantable medicaldevice, the location of the target area, the size of the patient, etc.As such, a medical practitioner is required to have a large inventory ofanchorage device wherein the anchorage devices include differenthemostatic agents and/or different amounts of hemostatic agents toaccommodate different types of implantable medical devices, differenttarget areas, different size patients, etc. This disclosure describes animprovement over these prior art technologies.

SUMMARY

New kits and methods are provided to help anchor or support animplantable medical device to surrounding tissue. In one embodiment, akit is provided that includes an anchorage device, such as, for example,a mesh substrate and a polymer that is fixed to the mesh substrate. Thepolymer comprises an active agent that is configured to elute over time.The kit further includes a hemostatic agent that is separate from themesh substrate and the polymer. The active agent is configured to reduceor prevent infection while the hemostatic agent prevents or reducesbleeding at a target site.

The mesh substrate is configured to deliver the active agent locally toprevent infections of implanted medical devices, such as, for example,implanted electronic devices. The hemostatic agent is configured to bedelivered to a target site before, during or after the mesh substrate isimplanted within a patient. In some embodiments, the mesh substrate iscoated with the polymer. In some embodiments, the polymer and the activeagent are soluble in organic solvents, such as, for example,tetrahydrofuran. In some embodiments, the polymer and the active agentare dissolved in an organic solvent and are then sprayed onto the meshsubstrate to provide a uniform coating. In some embodiments, the coatingis homogenous. It is envisioned that homogenous coatings may bebeneficial to provide more predictable results over coatings that arenot homogenous since degradation rates and elution rates for example, ofhomogenous coatings may be predicted more accurately than degradationrates and elution rates of coatings that are not homogenous. In someembodiments, the hemostatic agent is insoluble in organic solvents. Insome embodiments, the hemostatic agent is water soluble. In someembodiments, the polymer is a tyrosine polyarylate. In some embodiments,the active agent comprises at least one antibiotic. In some embodiments,the active agent comprises rifampin and minocycline. In someembodiments, the implanted electronic devices include pacemakers andneuromodulators.

In some embodiments, the hemostatic agent comprises one or more oftranexamic acid, collagen, oxidized cellulose and thrombin. In someembodiments, the hemostatic agent is provided in a solution. In someembodiments, the hemostatic agent is reconstituted at the time ofsurgery. In some embodiments, the hemostatic agent is configured tocontrol between about 20 cc and about 50 cc of blood. In someembodiments, the hemostatic agent is configured to control less than 20cc of blood. In some embodiments, the hemostatic agent is configured tocontrol more than 50 cc of blood. In some embodiments, the hemostaticagent is configured to be effective to control bleeding for about 5 daysto about 7 days. In some embodiments, the hemostatic agent is configuredto be effective to control bleeding less than 5 days. In someembodiments, the hemostatic agent is configured to be effective tocontrol bleeding for more than 7 days.

In some embodiments, the mesh substrate defines an envelope, pouch, orpocket in which, one side of the envelope, pouch, or pocket includes anopening to allow a device, such as, for example, the implantable medicaldevice to be inserted through the opening and into a cavity of theenvelope, pouch, or pocket. In some embodiments, the polymer covers allor a portion of the mesh substrate. In some embodiments, the polymeralso includes an active agent such that the active pharmaceutical agentelutes over time in the area surrounding or adjacent to the meshsubstrate. In some embodiments, the polymer including the active agentis applied to the mesh substrate such that the active agent elutes overtime in the area surrounding or adjacent to the mesh substrate.

Additional features and advantages of various embodiments will be setforth in part in the description that follows, and in part will beapparent from the description, or may be learned by practice of variousembodiments. The objectives and other advantages of various embodimentswill be realized and attained by means of the elements and combinationsparticularly pointed out in the description and appended claims.

BRIEF DESCRIPTION OF THE DRAWINGS

The present disclosure will become more readily apparent from thespecific description accompanied by the following drawings, in which:

FIG. 1 is a perspective view of components of a kit in accordance withthe principles of the present disclosure;

FIG. 2 is a front view of components of the kit shown in FIG. 1implanted in a patient;

FIG. 3 is a perspective view of a component of the kit shown in FIG. 1;

FIG. 4 is a perspective view of a component of the kit shown in FIG. 1;and

FIG. 5 is a perspective view of components of the kit shown in FIG. 1.

DETAILED DESCRIPTION

For the purposes of this specification and appended claims, unlessotherwise indicated, all numbers expressing quantities of ingredients,percentages or proportions of materials, and other numerical values usedin the specification and claims, are to be understood as being modifiedin al instances by the term “about.” Accordingly, unless indicated tothe contrary, the numerical parameters set forth in the followingspecification and attached claims are approximations that may varydepending upon the desired properties sought to be obtained by thepresent invention. At the very least, and not as an attempt to limit theapplication of the doctrine of equivalents to the scope of the claims,each numerical parameter should at least be construed in light of thenumber of reported significant digits and by applying ordinary roundingtechniques.

Notwithstanding the numerical ranges and parameters set forth herein,the broad scope of the invention are approximations, the numericalvalues set forth in the specific examples are reported as precisely aspossible. Any numerical value, however, inherently contains certainerrors necessarily resulting from the standard deviation found in theirrespective testing measurements. Moreover, all ranges disclosed hereinare to be understood to encompass any and all subranges subsumedtherein. For example, a range of “1 to 10” includes any and allsubranges between (and including) the minimum value of 1 and the maximumvalue of 10, that is, any and all subranges having a minimum value ofequal to or greater than 1 and a maximum value of equal to or less than10, e.g., 5.5 to 10.

Reference will now be made in detail to certain embodiments of theinvention, examples of which are illustrated in the accompanyingdrawings. While the invention will be described in conjunction with theillustrated embodiments, it will be understood that they are notintended to limit the invention to those embodiments. On the contrary,the invention is intended to cover al alternatives, modifications, andequivalents that may be included within the invention as defined by theappended claims.

This disclosure is directed to a kit 20 that include at least oneanchorage device. In some embodiments, the components of kit 20 can befabricated from biologically acceptable materials suitable for medicalapplications, including metals, synthetic polymers, allografts,xenografts, isografts, ceramics and bone material and/or theircomposites, depending on the particular application and/or preference ofa medical practitioner. For example, the components of kit 20,individually or collectively, can be fabricated from materials such asstainless steel alloys, commercially pure titanium, titanium alloys,Grade 5 titanium, super-elastic titanium alloys, cobalt-chrome alloys,stainless steel alloys, superelastic metallic alloys (e.g., Nitinol,super elasto-plastic metals, such as GUM METAL® manufactured by ToyotaMaterial Incorporated of Japan), ceramics and composites thereof such ascalcium phosphate (e.g., SKELITE™ manufactured by Biologix Inc.),thermoplastics such as polyaryletherketone (PAEK) includingpolyetheretherketone (PEEK), polyetherketoneketone (PEKK) andpolyetherketone (PEK), carbon-PEEK composites, PEEK-BaSO₄ polymericrubbers, polyethylene terephthalate (PET), fabric, silicone,polyurethane, siicone-polyurethane copolymers, polymeric rubbers,polyolefin rubbers, hydrogels, semi-rigid and rigid materials,elastomers, rubbers, themoplastic elastomers, thermoset elastomers,elastomeric composites, rigid polymers including polyphenylene,polyamide, polyamide, polyetherimide, polyethylene, tyrosinepolyarylate, epoxy, bone material including autograft, allograft,xenograft or transgenic cortical and/or corticocancellous bone, andtissue growth or differentiation factors, partially resorbablematerials, such as, for example, composites of metals and calcium-basedceramics, composites of PEEK and calcium based ceramics, composites ofPEEK with resorbable polymers, totally resorbable materials, such as,for example, calcium based ceramics such as calcium phosphate,tri-calcium phosphate (TCP), hydroxyapatite (HA)-TCP, calcium sulfate,or other resorbable polymers such as polylactide, polyglycolide,polytyrosine carbonate, polycaroplactone and their combinations.

Various components of kit 20 may have material composites, including theabove materials, to achieve various desired characteristics such asstrength, rigidity, elasticity, compliance, biomechanical performance,durability and radiolucency or imaging preference. The components of kit20, individually or collectively, may also be fabricated from aheterogeneous material such as a combination of two or more of theabove-described materials. The components of kit 20 may bemonolithically formed, integrally connected or include fasteningelements and/or instruments, as described herein.

Kit 20 includes a substrate, such as, for example, mesh substrate 22, asshown in FIG. 1. Substrate 22 is configured to be coupled to and/orapplied to a device, such as, for example, an implantable medical device24, as shown in FIG. 2. In some embodiments, substrate 22 is configuredto surround and/or enclose at least a portion of implantable medicaldevice 24, as discussed herein. Substrate 22 is configured to be securedto tissue to support implantable medical device 24 at a treatment site.

Substrate 22 can have a variety of different configurations, shapes andsizes. For example, substrate 22 can be provided with a size and shapeor other configuration that can provide the functionality of supportingand immobilizing implantable medical device 24 at a target site, suchas, for example, a treatment site within a patient's body, while alsoimproving the removability of substrate 22 after the treatment has beencompleted. In some embodiments, implantable medical device 24 can bedisposed within a pocket defined by substrate 22 and substrate 22 can beimplanted and secured to tissue at a desired treatment site within abody of a patient. As discussed herein, during implantation, scar tissuecan form at the treatment site and/or tissue can become ingrown withinsubstrate 22. After the treatment is completed, implantable medicaldevice 24 can remain in the patient, or can be removed from the patientleaving substrate implanted, as discussed herein. To remove substrate22, tissue that is ingrown within substrate 22 can be cut or otherwisedetached from substrate 22. In some embodiments, a portion of substrate22 may not be removable from the tissue and will remain implanted withinthe patient.

Substrate 22 may be formed with one or more biocompatible materials,which may be synthetic or naturally occurring. In some embodiments, theone or more biocompatible materials include, for example, polypropylene,polyester, polytetrafluoroethylene, polyamides, silicones, polysulfones,metals, alloys, titanium, stainless steel, shape memory metals (e.g.Nitinol), and/or combinations thereof.

In some embodiments, substrate 22 is configured to be implantedtemporarily within a body of a patient and/or is configured to beremoved (e.g., explanted) from the patient's body after a period oftime. In such embodiments, substrate 22 may include a non-biodegradablematerial and/or a non-bioresorbable material. For example, substrate 22may be made entirely from a non-biodegradable material and/or anon-bioresorbable material such that substrate 22 is made only from thenon-biodegradable material and/or non-bioresorbable material. In someembodiments, substrate 22 may include one or more non-biodegradableand/or a non-bioresorbable material and one or more biodegradable and/orresorbable material. In some embodiments, one side of substrate 22 mayinclude one or more non-biodegradable and/or a non-bioresorbablematerial and another side of substrate 22 can include one or morebiodegradable and/or resorbable material.

As used herein, the term “biodegradable” refers to, for example, amaterial that can be at least partially broken down or degraded by abodily fluid and discarded as waste from the body and/or a material thatcan be broken down or degraded by a living organism. Thus,“non-biodegradable” can refer to a material that cannot be broken downor degraded by a bodily fluid and/or cannot be broken down or degradedby a living organism. As used herein the term “resorbable” refers to,for example, a material that can be at least partially broken down ordegraded by a bodily fluid and assimilated within the body. Thus, a“non-resorbable” material as used herein can refer to, for example, amaterial that cannot be broken down or degraded by bodily fluid andassimilated within the body.

In some embodiments, the biocompatible biodegradable and/orbioresorbable material or materials may include polymeric and/ornon-polymeric materials, such as, for example, one or more poly(alpha-hydroxy acids), poly (lactide-co-glycolide) (PLGA), polylactide(PLA), poly(L-lactide), polyglycolide (PG), polyethylene glycol (PEG)conjugates of poly (alpha-hydroxy acids), polyorthoesters (POE),polyaspirins, polyphosphazenes, collagen, hydrolyzed collagen, gelatin,hydrolyzed gelatin, fractions of hydrolyzed gelatin, elastin, starch,pre-gelatinized starch, hyaluronic acid, chitosan, alginate, albumin,fibrin, vitamin E analogs, such as alpha tocopheryl acetate, d-alphatocopheryl succinate, D,L-lactide, or L-lactide, -caprolactone,dextrans, vinylpyrrolidone, polyvinyl alcohol (PVA), PVA-g-PLGA,PEGT-PBT copolymer (polyactive), methacrylates, poly(N-isopropylacrylamide), PEO-PPO-PEO (pluronics), PEO-PPO-PAAcopolymers, PLGA-PEO-PLGA, PEG-PLG, PLA-PLGA, poloxamer 407,PEG-PLGA-PEG triblock copolymers, POE, SAIB (sucrose acetateisobutyrate), polydioxanone, methylmethacrylate (MMA), MMA andN-vinylpyyrolidone, polyamide, oxycellulose, copolymer of glycolic acidand trimethylene carbonate, polyesteramides, tyrosine polyarylates,polyetheretherketone, polymethylmethacrylate, silicone, hyaluronic acid,chitosan, or combinations thereof. In one embodiment, substrate 22comprises Glycoprene, which is sold by Poly-Med, Inc. As used herein,the term “glycoprene” or “Glycoprene” refers to Glycoprene® orGlycoprene II®. Glycoprene® can refer to different variations of thematerial sold under the trade name Glycoprene®, such as, for example,Glycoprene® 6829, Glycoprene® 8609 and Glycoprene® 7027.

In some embodiments, the biocompatible non-biodegradable and/ornon-bioresorbable material or materials may include polymeric and/ornon-polymeric materials, such as, for example, polyurethane, polyester,polytetrafluoroethylene (PTFE),polyethylacrylate/polymethylmethacrylate, polylactide,polylactide-co-glycolide, polyamides, polydioxanone, polyvinyl chloride,polymeric or silicone rubber, collagen, thermoplastics, or combinationsthereof.

In some embodiments, substrate 22 is configured to be permanentlyimplanted within a body of a patient. In such embodiments, substrate 22may include a biodegradable material and/or a bioresorbable material.For example, substrate 22 may be made entirely from a biodegradablematerial and/or a bioresorbable material such that substrate 22 is madeonly from the biodegradable material and/or bioresorbable material.

In some embodiments, substrate 22 is web or fabric with a constructionof knitted, braided, woven or non-woven filaments or fibers F that areinterlocked in such a way to create a fabric or a fabric-like materialthat includes a matrix of filaments that define multiple pores P, asshown in FIG. 3. That is, the space between adjacent filaments or fibersF define pores P of the mesh. Pores P may be beneficial to allow tissuein-growth, for example. In some embodiments, apertures may be formed inthe mesh by cutting the filaments or fibers F to decrease the arealdensity (e.g., surface density) or mass of the mesh and/or furtherfacilitate tissue in-growth. In some embodiments, the apertures thatextend through the filaments or fibers F are larger than pores P definedby the filaments or fibers F.

In some embodiments, substrate 22 is provided in the form of a thinwalled structure, such as, for example, a wafer, sheet or tissue. Insome embodiments, the thin walled structure does not include any poresor apertures, in contrast to the mesh discussed herein. In someembodiments, the thin walled structure includes pores or apertures thatare smaller than the pores or apertures of the mesh discussed herein. Insome embodiments, the thin walled structure has a thickness that is lessthan a thickness of the mesh discussed herein. In some embodiments, thethickness of the thin walled structure is between about 0.001 inches andabout 0.1 inches.

In some embodiments, substrate 22 is a planar sheet, as shown in FIG. 1.In some embodiments, the planar sheet is in the form of a mesh. In someembodiments, the planar sheet is in the form of a thin walled structure.The planar sheet has a first side and an opposite second side, similarto a sheet of paper. The planar sheet can be manipulated about all oronly a portion of an implantable medical device, such as, for example,one of the implantable medical devices discussed herein. In someembodiments, the planar sheet is moldable or bendable about theimplantable medical device. That is, the planar sheet can be bentwithout breaking the planar sheet. In some embodiments, the planar sheetcan be manipulated to form a tube, for example. In some embodiments, theplanar sheet has a rigid configuration. That is, the planar sheet cannotbe bent without breaking the planar sheet. In some embodiments, theplanar sheet can be secured to tissue to support the implantable medicaldevice at the treatment site. The planar sheet can be variously shaped,such as, for example, circular, oval, oblong, triangular, rectangular,square, polygonal, irregular, uniform, non-uniform, variable and/ortapered.

In some embodiments, substrate 22 is a scaffold, a sponge, woven,non-woven, knitted or non-knitted. In some embodiments, substrate 22 canbe formed by extrusion.

In some embodiments, substrate 22 is a pocket or envelope in whichimplantable medical device 24 can be at least partially disposed. Thatis, substrate 22 is a pouch, bag, covering, shell, or receptacle. Forexample, substrate 22 can include a first piece 22 a and a second piece22 b that is joined with first piece 22 a, as shown in FIG. 3. First andsecond pieces 22 a, 22 b are joined to form the pocket or envelope. Insome embodiments, first and second pieces 22 a, 22 b are joined alongthree sides of the pocket or envelope to form a cavity C. First andsecond pieces 22 a, 22 b are not joined at a fourth side of the pocketor envelope to define an opening O such that implantable medical device24 can be inserted through opening O and into cavity C to enclose,encase or surround all or a portion of implantable medical device 24within cavity C. In some embodiments, first and second pieces 22 a, 22 bare joined with one another along three sides of the pocket or envelopeby heat, ultrasonically, bonding, knitting, or adhesive. In someembodiment, the pocket or envelope is monolithically formed by moldingthe pocket or envelope or producing the pocket or envelope by 3Dprinting, for example.

In some embodiments, first and second pieces 22 a, 22 b are portions ofa single sheet that is bent to produce a fold at one end of the pocketor envelope, as shown in FIG. 4. First and second pieces 22 a, 22 b arejoined along sides of the pocket or envelope that extend transverse tothe fold such that the fold and the sides of the pocket or envelope donot have any openings. First and second pieces 22 a, 22 b are not joinedat an end of the pocket or envelope opposite the fold to define anopening at the end such that a medical device can be inserted throughthe opening and into a cavity defined by inner surfaces of first andsecond pieces 22 a, 22 b.

In some embodiments, first and second pieces 22 a, 22 b each include amesh discussed herein. In some embodiments, first piece 22 a includes amesh including pores having a first size and second piece 22 b includesa mesh including pores having a second size, wherein the first size isdifferent than the first size. In some embodiments, the first size isgreater than the second size. In some embodiments, the first size isless than the second size. In some embodiments, first and second pieces22 a, 22 b each include a thin walled structure discussed herein. Insome embodiments one of first and second pieces 22 a, 22 b includes amesh discussed herein and the other one of first and second pieces 22 a,22 b includes a thin walled structure discussed herein that does nothave any pores or apertures.

In some embodiments, first and second pieces 22 a, 22 b are formed fromthe same material. In some embodiments one of first and second pieces 22a, 22 b is formed from a first material, such as, for example, one ofthe materials discussed herein, and the other one of first and secondpieces 22 a, 22 b is made from a second material, such as, for example,one of the materials discussed herein, wherein the second material isdifferent than the first material. For example, first piece 22 a may beformed from a biodegradable and/or bioresorbable material and secondpiece 22 b may be formed from a non-biodegradable and/ornon-bioresorbable material, or vice versa. In some embodiments, firstand second pieces 22 a, 22 b are each formed from a biodegradable and/orbioresorbable material, wherein the biodegradable and/or bioresorbablematerials degrade and/or resorb at the same rate. In some embodiments,first and second pieces 22 a, 22 b are formed from differentbiodegradable and/or bioresorbable materials, wherein one of thebiodegradable and/or bioresorbable materials degrades and/or resorbsmore quickly than the other biodegradable and/or bioresorbable material.

In some embodiments, first and second pieces 22 a, 22 b each include asingle layer of material, such as, for example, one of the materialsdiscussed herein. In some embodiments, at least one of first and secondpieces 22 a, 22 b includes multiple layers. In some embodiments, themultiple layers include more than one layer of the mesh discussedherein. In some embodiments, the multiple layers include more than onelayer of the thin walled structure discussed herein. In someembodiments, the multiple layers include one or more layer of the meshdiscussed herein and one or more layer of the thin walled structurediscussed herein. In some embodiments, the multiple layers include oneor more layer of the mesh discussed herein and one or more layer of thethin walled structure discussed herein, wherein one of the layers ofmesh is positioned between two layers of the thin walled structure. Insome embodiments, the multiple layers include one or more layer of themesh discussed herein and one or more layer of the thin walled structurediscussed herein, wherein one of the layers of thin walled structure ispositioned between two layers of the mesh.

In some embodiments, substrate 22 may include a polymer that is appliedto and/or coats at least a portion of substrate 22, wherein the polymerincludes an active agent, such as, for example an active pharmaceuticalagent. That is, the active pharmaceutical agent is applied to substrate22 via the polymer. In some embodiments, the polymer is soluble inorganic solvents, such as, for example, tetrahydrofuran. In someembodiments, the active pharmaceutical agent is also soluble in organicsolvents, such as, for example, tetrahydrofuran. In some embodiments,the polymer and the active pharmaceutical agent are dissolved in anorganic solvent and the organic solvent with the dissolved polymer andactive pharmaceutical agent is sprayed onto substrate 22 to provide auniform coating. In some embodiments, the polymer includes acombination, blend or mixture of polymers. In some embodiments, thepolymer is configured to degrade within a patient and releases theactive pharmaceutical agent as the polymer degrades. In someembodiments, the degradation rate of the polymer is known or can bepredicted to allow a medical practitioner to select a polymer or aquantity of polymer that is applied to substrate 22 to produce substrate22 that is customized to elute a selected quantity of the activepharmaceutical agent at a selected rate over a selected period of time.For example, the polymer may be selected to elute a selected quantity ofthe active pharmaceutical agent per hour or day for a selected number ofdays or hours.

In some embodiments, the polymer is selected from the group consistingof polylactic acid, polyglycolic acid, poly(L-lactide),poly(D,L-lactide)polyglycolic acid[polyglycolide],poly(L-lactide-co-D,L-lactide), poly(L-lactide-co-glycolide), poly(D,L-lactide-co-glycolide), poly(glycolide-co-trimethylene carbonate),poly(D,L-lactide-co-caprolactone), poly(glycolide-co-caprolactone),polyethylene oxide, polydioxanone, polypropylene fumarate, poly(ethylglutamate-co-glutamic acid), poly(tert-butyloxy-carbonylmethylglutamate), polycaprolactone, polycaprolactone co-butylacrylate,polyhydroxybutyrate, copolymers of polyhydroxybutyrate,poly(phosphazene), poly(phosphate ester), poly(amino acid),polydepsipeptides, maleic anhydride copolymers, polyiminocarbonates,poly[(97.5% dimethyl-trimethylene carbonate)-co-(2.5% trimethylenecarbonate)], poly(orthoesters), tyrosine-derived polyarylates,tyrosine-derived polycarbonates, tyrosine-derivedpolyiminocarbonates,tyrosine-derivedpolyphosphonates, polyethylene oxide, polyethyleneglycol, polyalkylene oxides, hydroxypropylmethylcellulose,polysaccharides such as hyaluronic acid, chitosan and regeneratecellulose. In some embodiments, the polymer may include combinations,blends or mixtures of the polymers discussed herein.

In some embodiments, the polymer is a polyarylate. In some embodiments,the polymer is a tyrosine-derived polyarylate. In some embodiments, thetyrosine-derived polyarylate is p(DTE co X % DT succinate), where X isabout 10% to about 30%. In some embodiments, the tyrosine-derivedpolyarylate is p(DTE co X % DT succinate), where X ranges from about26.5% to about 28.5%. In some embodiments, the tyrosine-derivedpolyarylate is p(DTE co X % DT succinate), where X is about 27.5%. Insome embodiments, the polymer is P22-27.5 DT.

As used herein, DTE is the diphenol monomer desaminotyrosyl-tyrosineethyl ester; DTBn is the diphenol monomer desaminotyrosyl-tyrosinebenzyl ester; DT is the corresponding free acid form, namelydesaminotyrosyl-tyrosine. BTE is the diphenol monomer 4-hydroxy benzoicacid-tyrosyl ethyl ester; BT is the corresponding free acid form, namely4-hydroxy benzoic acid-tyrosine.

P22-XX is a polyarylate copolymer produced by condensation of DTE andDTBn with succinic acid followed by removal of benzyl group. P22-10,P22-15, P22-20, P22-XX, etc., represents copolymers different percentageof DT (i.e., 10, 15, 20 and % DT, etc.). In some embodiments, thepolymer is produced by condensation of DTBn with succinic acid followedby removal of benzyl group.

In some embodiments, the polymer includes one or more polyarylates thatare copolymers of desaminotyrosyl-tyrosine (DT) and andesaminotyrosyl-tyrosyl ester (DT ester), wherein the copolymercomprises from about 0.001% DT to about 80% DT and the ester moiety canbe a branched or unbranched alkyl, alkylaryl, or alkylene ether grouphaving up to 18 carbon atoms, any group of which can, optionally have apolyalkylene oxide therein. Similarly, another group of polyarylates arethe same as the foregoing but the desaminotyrosyl moiety is replaced bya 4-hydroxybenzoyl moiety. In some embodiments, the DT or BT contentsinclude those copolymers with from about 1% to about 30%, from about 5%to about 30% from about 10 to about 30% DT or BT. In some embodiments,the diacids (used informing the polyarylates) include succinate,glutarate and glycolic acid.

In some embodiments, the polymer includes one or more biodegradable,resorbable polyarylates and polycarbonates. These polymers, include, butare not limited to, BTE glutarate, DTM glutarate, DT propylamideglutarate, DT glycineamide glutarate, BTE succinate, BTM succinate, BTEsuccinate PEG, BTM succinate PEG, DTM succinate PEG, DTM succinate, DTN-hydroxysuccinimide succinate, DT glucosamine succinate, DT glucosamineglutarate, DT PEG ester succinate, DT PEG amide succinate, DT PEG esterglutarate, DT PEG ester succinate, DTMB P(Desaminotyrsoyl tyrosinemethylparaben ester-glutarate), and DTPP P(Desaminotyrsoyl tyrosinepropylparaben ester-glutarate).

In some embodiments, the polymer is one more polymers from the DTE-DTsuccinate family of polymers, e.g., the P22-xx family of polymers havingfrom 0-50%, 5-50%, 5-40%, 1-30% or 10-30% DT, including but not limitedto, about 1, 2, 5, 10, 15, 20, 25, 27.5, 30, 35, 40%, 45% and 50% DT. Insome embodiments, the polymer is P22-27.5 DT.

In some embodiments, the polymer has diphenol monomer units that arecopolymerized with an appropriate chemical moiety to form a polyarylate,a polycarbonate, a polyiminocarbonates, a polyphosphate or any otherpolymer.

In some embodiments, the polymer is tyrosine-based polyarylate. In someembodiments, the polymer includes blends and copolymers withpolyalkylene oxides, including polyethylene glycol (PEG).

In some embodiments, the polymer can have from 0.1-99.9% PEG diacid topromote the degradation process. In some embodiments, the polymerincludes blends of polyarylates or other biodegradable polymers withpolyarylates.

The polymer is configured to release the active pharmaceutical agentover time, as discussed herein. In some embodiments, the polymer isconfigured to release the active pharmaceutical agent over a time periodranging from about 1 hour to about 168 hours. In some embodiments, thepolymer is configured to release the active pharmaceutical agent over atime period ranging from 1 hour to 72 hours. In some embodiments, thepolymer is configured to release the active pharmaceutical agent over atime period ranging from 1 hour to 24 hours.

In some embodiments, the polymer is configured to release the activepharmaceutical agent over time in an area surrounding or adjacent tosubstrate 22 (such as, for example, within the “pocket” or within 3inches in all dimensions). In some embodiments, the polymer isconfigured to release the active pharmaceutical agent for up to 30hours. In some embodiments, the polymer is configured to release betweenabout 40% and about 100% of the active pharmaceutical agent over aperiod of at least about 30 hours. In some embodiments, the polymer isconfigured to release between about 60% and about 100% of the activepharmaceutical agent over a period of at least about 30 hours. In someembodiments, the polymer is configured to release between about 65% andabout 100% of the active pharmaceutical agent over a period of at leastabout 36 hours. In some embodiments, the polymer is configured torelease between about 80% and about 100% of the active pharmaceuticalagent over a period of at least about 36 hours. In some embodiments, thepolymer is configured to release between about 60% and about 100% of theactive pharmaceutical agent over a period of at least about 48 hours. Insome embodiments, the polymer is configured to release between about 80%and about 100% of the active pharmaceutical agent over a period of atleast about 48 hours. In some embodiments, the polymer is configured torelease between about 60% and about 100% of the active pharmaceuticalagent over a period of at least about 60 hours. In some embodiments, thepolymer is configured to release between about 80% and about 100% of theactive pharmaceutical agent over a period of at least about 60 hours. Insome embodiments, the polymer is configured to release between about 80%and about 100% of the active pharmaceutical agent within 48 hours. Insome embodiments, the polymer is configured to release between about 80%and about 100% of the active pharmaceutical agent within 24 hours.

In some embodiments, the polymer is configured to release no more than60% of the active pharmaceutical agent within 24 hours. In someembodiments, the polymer is configured to release no more than 90% ofthe active pharmaceutical agent after 60 hours. In some embodiments, thepolymer is configured to release no more than 50% of the activepharmaceutical agent within 12 hours. In some embodiments, the polymeris configured to release between about 40% and about 90% of the activepharmaceutical agent between 12 and 24 hours. In some embodiments, thepolymer is configured to release between about 60% and about 100% of theactive pharmaceutical agent between 24 and 36 hours. In someembodiments, the polymer is configured to release between about 65% andabout 100% of the active pharmaceutical agent between 36 and 48 hours.In some embodiments, the polymer is configured to release between about70% and about 100% of the active pharmaceutical agent between 48 and 60hours.

Substrate 22 may be coated with single or multiple coating layers of thepolymer, depending on, for example, the amount of the activepharmaceutical agent to be delivered and desired release rate. Eachlayer of the polymer may contain the same or different amounts of theactive pharmaceutical agent. For example, a first layer of the polymermay contain the active pharmaceutical agent, while the second layer ofthe polymer contains either no active pharmaceutical agent or a lowerconcentration of the active pharmaceutical agent. As another example, afirst layer of the polymer may comprise the active pharmaceutical agentin a first polymer, while the second layer of the polymer comprises theactive pharmaceutical agent in a second polymer that is different thanthe first polymer.

In embodiments discussed herein wherein substrate 22 is a planar sheet,a first polymer can be applied to the top surface of the sheet and asecond polymer can be applied to the bottom surface of the sheet. Insome embodiments, the first and second polymers are different polymers.In some embodiments, the first and second polymers release the activepharmaceutical agent at different rates and/or over different lengths oftime. In some embodiments, the first and second polymers are differentpolymers, and the first polymer includes a first amount of the activepharmaceutical agent and the second polymer includes a second amount ofthe active pharmaceutical agent, the first amount being different thanthe second amount. In some embodiments, the first and second polymersare the same polymer, wherein the first polymer includes a first amountof the active pharmaceutical agent and the second polymer includes asecond amount of the active pharmaceutical agent, the first amount beingdifferent than the second amount.

In embodiments discussed herein wherein substrate 22 is a pocket orenvelope, a first polymer can be applied to first piece 22 a and asecond polymer can be applied to second piece 22 b. In some embodiments,the first and second polymers are different polymers. In someembodiments, the first and second polymers release the activepharmaceutical agent at different rates and/or over different lengths oftime. In some embodiments, the first and second polymers are differentpolymers, and the first polymer includes a first amount of the activepharmaceutical agent and the second polymer includes a second amount ofthe active pharmaceutical agent, the first amount being different thanthe second amount. In some embodiments, the first and second polymersare the same polymer, wherein the first polymer includes a first amountof the active pharmaceutical agent and the second polymer includes asecond amount of the active pharmaceutical agent, the first amount beingdifferent than the second amount. In some embodiments, a first polymeris applied to the outer surfaces of first and second pieces 22 a, 22 band a second polymer is applied to the inner surfaces of first andsecond pieces 22 a, 22 b, wherein the first polymer includes a firstamount of the active pharmaceutical agent and the second polymerincludes a second amount of the active pharmaceutical agent, the firstamount being different than the second amount. In some embodiments, thefirst amount is more than the second amount. In some embodiments, thefirst amount is less than the second amount.

In some embodiments, the polymer and/or the active pharmaceutical agentis/are free of hemostatic agents, such as, for example, the hemostaticagents discussed herein, such that substrate 22 does not include anyhemostatic agents. In some embodiments, the active pharmaceutical agentcan include one or a combination of active pharmaceutical ingredients,such as, for example, anesthetics, antibiotics, anti-inflammatoryagents, procoagulants agents, fibrosis-inhibiting agents, antiseptics,anti-scanning agents, leukotriene inhibitors/antagonists, cell growthinhibitors and mixtures thereof. In some embodiments, the activepharmaceutical ingredient is an antibiotic. In some embodiments, theantibiotic is selected from the group consisting of rifampin andminocycline and mixtures thereof.

Examples of non-steroidal anti-inflammatories include, but are notlimited to, naproxen, ketoprofen, ibuprofen as well as diclofenac;celecoxib; sulindac; diflunisal; piroxicam; indomethacin; etodolac;meloxicam; r-flurbiprofen; mefenamic; nabumetone; tolmetin, and sodiumsalts of each of the foregoing; ketorolac bromethamine; ketorolacbromethamine tromethamine; choline magnesium trisalicylate; rofecoxib;valdecoxib; lumiracoxib; etoricoxib; aspirin; salicylic acid and itssodium salt; salicylate esters of alpha, beta, gamma-tocopherols andtocotrienols (and all their d,1, and racemic isomers); and the methyl,ethyl, propyl, isopropyl, n-butyl, sec-butyl, t-butyl, esters ofacetylsalicylic acid.

Examples of anesthetics include, but are not limited to, licodaine,bupivacaine, and mepivacaine. Further examples of analgesics,anesthetics and narcotics include, but are not limited to acetaminophen,clonidine, benzodiazepine, the benzodiazepine antagonist flumazenil,lidocaine, tramadol, carbamazepine, meperidine, zaleplon, trimipraminemaleate, buprenorphine, nalbuphine, pentazocain, fentanyl, propoxyphene,hydromorphone, methadone, morphine, levorphanol, and hydrocodone. Localanesthetics have weak antibacterial properties and can play a dual rolein the prevention of acute pain and infection.

Examples of antibacterial agents or antimicrobials include, but are notlimited to, triclosan, chlorohexidine and other cationic biguanides,rifampin, minocycline (or other tetracycline derivatives), vancomycin,gentamycin; gendine; genlenol; genfoctol; cofoctol; cephalosporins andthe like. Further antibacterial agents or antimicrobials includeaztreonam; cefotetan and its disodium salt; loracarbef; cefoxitin andits sodium salt; cefazoin and its sodium salt; cefador; ceftibuten andits sodium salt; ceftizoxime; ceftizoxime sodium salt; cefoperazone andits sodium salt; cefuroxime and its sodium salt; cefuroxime axetil;cefprozil; ceftazidime; cefotaxime and its sodium salt; cefadroxil;ceftazidime and its sodium salt; cephalexin; hexachlorophene;cefamandole nafate; cefepime and its hydrochloride, sulfate, andphosphate salt; cefdinir and its sodium salt; ceftriaxone and its sodiumsalt; cefixime and its sodium salt; cetylpyridinium chloride; ofoxacin;linexolid; temafloxacin; fleroxacin; enoxacin; gemifloxacin;lomefioxacin; astreonam; tosufoxacin; clinafoxacin; cefpodoximeproxetil; chloroxylenol; methylene chloride, iodine and iodophores(povidone-iodine); nitrofurazone; meropenem and its sodium salt;imipenem and its sodium salt; cilastatin and its sodium salt;azithromycin; clarithromycin; dirithromycin; erythromycin andhydrochloride, sulfate, or phosphate salts ethylsuccinate, and stearateforms thereof, clindamycin; clindamycin hydrochloride, sulfate, orphosphate salt; lincomycin and hydrochloride, sulfate, or phosphate saltthereof, tobramycin and its hydrochloride, sulfate, or phosphate salt;streptomycin and its hydrochloride, sulfate, or phosphate salt;vancomycin and its hydrochloride, sulfate, or phosphate salt; neomycinand its hydrochloride, sulfate, or phosphate salt; acetyl sufisoxazole;colistimethate and its sodium salt; quinupristin; dalfopristin;amoxicillin; ampicilin and its sodium salt; clavulanic acid and itssodium or potassium salt; penicillin G; penicillin G benzathine, orprocaine salt; penicillin G sodium or potassium salt; carbenicillin andits disodium or indanyl disodium salt; piperacillin and its sodium salt;α-terpineol; thymol; taurinamides; nitrofurantoin; silver-sulfadiazine;hexetidine; methenamine; aldehydes; azylic acid; silver; benzylperoxide; alcohols; carboxylic acids; salts; nafcillin; ticarcillin andits disodium salt; sulbactam and its sodium salt; methylisothiazolone,moxifloxacin; amifloxacin; pefloxacin; nystatin; carbepenems; lipoicacids and its derivatives; beta-lactams antibiotics; monobactams;aminoglycosides; microlides; lincosamides; glycopeptides; tetracyclines;chloramphenicol; quinolones; fucidines; sulfonamides; macrolides;ciprofloxacin; ofloxacin; levofloxacins; teicoplanin; mupirocin;norfloxacin; sparfloxacin; ketolides; polyenes; azoles; penicillins;echinocandines; nalidixic acid; rifamycins; oxalines; streptogramins;lipopeptides; gatifloxacin; trovafloxacin mesylate; alatrofloxacinmesylate; trimethoprims; sulfamethoxazole; demeclocydine and itshydrochloride, sulfate, or phosphate salt; doxycycline and itshydrochloride, sulfate, or phosphate salt; minocycline and itshydrochloride, sulfate, or phosphate salt; tetracycline and itshydrochloride, sulfate, or phosphate salt; oxytetracycline and itshydrochloride, sulfate, or phosphate salt; chlortetracycline and itshydrochloride, sulfate, or phosphate salt; metronidazole; dapsone;atovaquone; rifabutin; linezolide; polymyxin B and its hydrochloride,sulfate, or phosphate salt; sulfacetamide and its sodium salt; andclarithromycin (and combinations thereof). In some embodiments, thepolymer may contain rifampin and another antimicrobial agent, such as,for example, an antimicrobial agent that is a tetracycline derivative.In some embodiments, the polymer contains a cephalosporin and anotherantimicrobial agent. In some embodiments, the polymer containscombinations including rifampin and minocycline, rifampin andgentamycin, and rifampin and minocycline.

When a mixture of two antibiotics is used, they generally present in aratio ranging from about 10:1 to about 1:10. In some embodiments, amixture of rifampin and minocycline are used. In those embodiments, aratio of rifampin to minocycline ranges from about 52 to about 2:5. Inother embodiments, the ratio of rifampin to minocycline is about 1:1.

Examples of antifungals include amphotericin B; pyrimethamine;flucytosine; caspofungin acetate; fluconazole; griseofulvin; terbinafineand its hydrochloride, sulfate, or phosphate salt; amorolfine; triazoles(Voriconazole); flutrimazole; cilofungin; LY303366 (echinocandines);pneumocandin; imidazoles; omoconazole; terconazole; fluconazole;amphotericin B, nystatin, natamycin, liposomal amptericin B, liposomalnystatins; griseofulvin; BF-796; MTCH 24; BTG-137586; RMP-7/AmphotercinB; pradimicins; benanomicin; ambisome; ABLC; ABCD; Nikkomycin Z;flucytosine; SCH 56592; ER30346; UK 9746; UK 9751; T 8581; LY121019;ketoconazole; micronazole; clotrimazole; econazole; ciclopirox;naftifine; and itraconazole.

In some embodiments, the active pharmaceutical ingredient includeskeflex, acyclovir, cephradine, malphalen, procaine, ephedrine,adriamycin, daunomycin, plumbagin, atropine, quinine, digoxin,quinidine, biologically active peptides, cephradine, cephalothin,cis-hydroxy-L-proline, melphalan, penicillin V, aspirin, nicotinic acid,chemodeoxycholic acid, chlorambucil, paclitaxel, sirolimus,cyclosporins, 5-fluorouracil and the like.

In some embodiments, the active pharmaceutical ingredient includes oneor more ingredients that act as angiogenensis inhibitors or inhibit cellgrowth such as epidermal growth factor, PDGF, VEGF, FGF (fibroblastgrowth factor) and the like. These ingredients include anti-growthfactor antibodies (neutrophilin-1), growth factor receptor-specificinhibitors such as endostatin and thalidomide. Examples of usefulproteins include cell growth inhibitors such as epidermal growth factor.

Examples of anti-inflammatory compounds include, but are not limited to,anecortive acetate; tetrahydrocortisol, 4,9(11)-pregnadien-17a,21-diol-3,20-dione and its -21-acetate salt; 111-epicortisol;17α-hydroxyprogesterone; tetrahydrocortexolone; cortisona; cortisoneacetate; hydrocortisone; hydrocortisone acetate; fludrocortisone;fludrocortisone acetate; fludrocortisone phosphate; prednisone;prednisolone; prednisolone sodium phosphate; methylprednisolone;methylprednisolone acetate; methylprednisolone, sodium succinate;triamcinolone; triamcinolone-16,21-diacetate; triamcinolone acetonideand its -21-acetate, -21-disodium phosphate, and -21-hemisuccinateforms; triamcinolone benetonide; triamcinolone hexacetonide;fluocinolone and fluocinolone acetate; dexamethasone and its-21-acetate,-21-(3,3-dimethylbutyrate), -21-phosphate disodium salt,-21-diethylaminoacetate, -21-isonicotinate, -21-dipropionate, and-21-palmitate forms; betamethasone and its -21-acetate, -21-adamantoate,-17-benzoate, -17,21-dipropionate, -17-valerate, and -21-phosphatedisodium salts; beclomethasone; beclomethasone dipropionate;diflorasone; diflorasone diacetate; mometasone furoate; andacetazolamide.

Examples of leukotriene inhibitors/antagonists include, but are notlimited to, leukotriene receptor antagonists such as acitazanolast,iralukast, montelukast, pranlukast, verlukast, zafirlukast, andzileuton.

In some embodiments, the active pharmaceutical ingredient includessodium 2-mercaptoethane sulfonate (“MESNA”). MESNA has been shown todiminish myofibroblast formation in animal studies of capsularcontracture with breast implants [Ajmal et al. (2003) Plast. Reconstr.Surg. 112:1455-1461] and may thus act as an anti-fibrosis agent.

Procoagulants include, but are not limited to, zeolites, thrombin, andcoagulation factor concentrates.

In some embodiments, the amount of the active pharmaceutical ingredientthat is applied to substrate 22 via the polymer ranges between about 0.3to about 150 micrograms/cm². In other embodiments, the amount of theactive pharmaceutical ingredient that is applied to substrate 22 via thepolymer ranges between about 0.6 to about 1.4 micrograms/cm². In yetother embodiments, the amount of the active pharmaceutical ingredientthat is applied to substrate 22 via the polymer ranges between about0.85 to about 1.20 micrograms/cm². In yet further embodiments, theamount of the active pharmaceutical ingredient that is applied tosubstrate 22 via the polymer ranges between about 0.90 to about 1.10micrograms/cm². In yet further embodiments, the amount of the activepharmaceutical ingredient that is applied to substrate 22 via thepolymer ranges between about 50 to about 150 micrograms/cm². In yetfurther embodiments, 62 micrograms/cm² of the active pharmaceuticalingredient is applied to substrate 22 via the polymer. In yet furtherembodiments, 140 micrograms/cm² of the active pharmaceutical ingredientis applied to substrate 22 via the polymer.

In other embodiments, the active pharmaceutical ingredient includesrifampin and minocycline and the amount of each of rifampin andminocycline that is applied to substrate 22 via the polymer rangesbetween about 0.6 to about 1.4 micrograms/cm². In yet other embodiments,the amount of each of rifampin and minocycline that is applied tosubstrate 22 via the polymer ranges between about 0.85 to about 1.20micrograms/cm². In yet further embodiments, the amount of each ofrifampin and minocycline that is applied to substrate 22 via the polymerranges between about 0.90 to about 1.10 micrograms/cm².

The active pharmaceutical agent may include any of the activepharmaceutical ingredients discussed herein. Doses of the activepharmaceutical ingredients discussed herein are known and the amounts ofany single active pharmaceutical ingredient to include in the polymercan readily be surmised. Any pharmaceutically acceptable form of theactive pharmaceutical ingredients discussed herein can be employed insubstrate 22 and/or the polymer, e.g., the free base or apharmaceutically acceptable salt or ester thereof. Pharmaceuticallyacceptable salts, for instance, include sulfate, lactate, acetate,stearate, hydrochloride, tartrate, maleate, citrate, phosphate and thelike.

In embodiments discussed herein wherein anchorage device 20 is a planarsheet, the polymer including the active pharmaceutical agent can beapplied to at least one of the top and bottom surfaces of the sheet viathe polymer. That is, the polymer may be applied to both the top andbottom surfaces, or only one of the top and bottom surfaces. In someembodiments, a first polymer including an active pharmaceutical agent isapplied to the top surface and a second polymer including an activepharmaceutical ingredient is applied to the bottom surface, wherein thefirst polymer includes an active pharmaceutical ingredient that isdifferent than the active pharmaceutical ingredient in the secondpolymer. In some embodiments, a first polymer including an activepharmaceutical ingredient is applied to the top surface and a secondpolymer including an active pharmaceutical ingredient is applied to thebottom surface, wherein the active pharmaceutical ingredient in thefirst polymer includes a different amount of active pharmaceuticalingredient than the second polymer.

In embodiments discussed herein wherein substrate 22 is a planar sheet,the polymer including the active pharmaceutical ingredient can beapplied to the top surface and the bottom surface is free of thepolymer. In some embodiments, one of the top and bottom surfacesincludes the polymer including the active pharmaceutical ingredient andthe other of the top and bottom surfaces is free of the polymer. In someembodiments, one of the top and bottom surfaces includes the polymerincluding the active pharmaceutical ingredient and the other of the topand bottom surfaces includes a polymer that is free of any activepharmaceutical ingredients.

In embodiments discussed herein wherein substrate 22 is a planar sheet,a first polymer can be applied to one of the top and bottom surfaces anda second polymer can be applied to the other one of the top and bottomsurfaces. In some embodiments, at least one of the first and secondpolymers includes a plurality of discrete layers, such as, for example,a first layer, a second layer, a third layer, a fourth layer, a fifthlayer, etc. In some embodiments, at least one of the layers includes apolymer that is different than a polymer that forms at least one of theother layers.

In some embodiments, the layers each include the same polymer. In someembodiments, the contents of the layers alternate. For example, in someembodiments, the first layer includes the active pharmaceutical agent,the second layer is free of the active pharmaceutical agent, the thirdlayer includes the active pharmaceutical agent, the fourth layer is freeof the active pharmaceutical agent and the fifth layer includes theactive pharmaceutical agent. In some embodiments, the layers eachinclude the active pharmaceutical agent, wherein the amount of theactive pharmaceutical agent in each layer is the same or different.

In embodiments discussed herein wherein substrate 22 is a pocket orenvelope, the polymer including the active pharmaceutical agent can beapplied to at least one of first piece 22 a and second piece 22 b. Insome embodiments, only one of first and second pieces 22 a, 22 bincludes the polymer having the active pharmaceutical ingredient. Insome embodiments, the polymer including the active pharmaceuticalingredient is applied only to the outer surfaces of first and secondpieces 22 a, 22 b. That is, the inner surfaces of first and secondpieces 22 a, 22 b that define cavity C do not have the polymer appliedthereto. In some embodiments, the polymer including the activepharmaceutical ingredient is applied only to the inner surfaces of firstand second pieces 22 a, 22 b. That is, the outer surfaces of first andsecond pieces 22 a, 22 b do not have the polymer applied thereto. Insome embodiments, the polymer including the active pharmaceuticalingredient is applied only to the inner surface of one of first andsecond pieces 22 a, 22 b and to the outer surface of the other one offirst and second pieces 22 a, 22 b.

In embodiments discussed herein wherein substrate 22 is a pocket orenvelope, a polymer having a first active pharmaceutical ingredient canbe applied to first piece 22 a and a polymer having a second activepharmaceutical ingredient can be applied to second piece 22 b, whereinthe active pharmaceutical ingredient in the second polymer is differentthan the active pharmaceutical ingredient in the first polymer. In someembodiments, a first polymer including an active pharmaceuticalingredient is applied to the outer surfaces of first and second pieces22 a, 22 b and a second polymer including an active pharmaceuticalingredient is applied to the inner surfaces of first and second pieces22 a, 22 b, wherein the active pharmaceutical ingredient in the secondpolymer is different than the active pharmaceutical ingredient in thesecond polymer.

In embodiments discussed herein wherein substrate 22 is a pocket orenvelope, a first polymer can be applied to one of first and secondpieces 22 a, 22 b and a second polymer can be applied to the other oneof first and second pieces 22 a, 22 b. In some embodiments, the firstand second polymers are the same polymer. In some embodiments, the firstand second polymers are different polymers. In some embodiments, thefirst and second polymers each include the active pharmaceuticalingredient, wherein one of the first and second polymers includes moreof the active pharmaceutical ingredient than the other of the first andsecond polymers.

In embodiments discussed herein wherein anchorage device 20 is a pocketor envelope, a first polymer can be applied to first piece 22 a and asecond polymer can be applied to second piece 22 b. In some embodiments,the first and second polymers are different polymers. In someembodiments, the first and second polymers release the activepharmaceutical ingredient at different rates and/or over differentlengths of time. In some embodiments, the first and second polymers aredifferent polymers, and the first polymer includes a first amount of theactive pharmaceutical ingredient and the second polymer includes asecond amount of the active pharmaceutical ingredient, the first amountbeing different than the second amount. In some embodiments, the firstand second polymers are the same polymer, wherein the first polymerincludes a first amount of the active pharmaceutical ingredient and thesecond polymer includes a second amount of the active pharmaceuticalingredient, the first amount being different than the second amount. Insome embodiments, a first polymer is applied to the outer surfaces offirst and second pieces 22 a, 22 b and a second polymer is applied tothe inner surfaces of first and second pieces 22 a, 22 b, wherein thefirst polymer includes a first amount of the active pharmaceuticalingredient and the second polymer includes a second amount of the activepharmaceutical ingredient, the first amount being different than thesecond amount. In some embodiments, the first amount is more than thesecond amount. In some embodiments, the first amount is less than thesecond amount.

In some embodiments, the active pharmaceutical ingredient is configuredto elute/release from the polymer into an area surrounding or adjacentto substrate 22 to reduce the amount of associated post-surgicalcomplications that can occur with such implantable medical devices, suchas, for example, post-implant infection, pain, excessive scar tissueformation and shrinkage of the prosthesis or mesh, excessive scar tissueformation, limited patient mobility, and/or chronic pain. In someembodiments, the active pharmaceutical ingredient is configured toelute/release from the polymer into an area surrounding or adjacent tosubstrate 22 to prevent surgery-related complications associated withthe implantable medical device (such as to the “pocket” surrounding thedevice). For example, an anesthetic agent can be eluted into thesurrounding bodily tissue, bodily fluid, or systemic fluid, to attenuatepain experienced at the implantation site. In another example, replacingthe anesthetic agent with an anti-inflammatory agent can reduce theswelling and inflammation associated implantation of substrate 22. Inyet another example, an antimicrobial agent can be provided at a rate ofdrug release sufficient to prevent or reduce colonization of substrate22, the implantable medical device and/or the surgical implantation siteby bacteria, for example, for at least the period following surgerynecessary for initial healing of the surgical incision.

In some embodiments, the active pharmaceutical ingredient may be elutedfor up to 30 days. In some embodiments, between about 40% and about 100%of the active pharmaceutical ingredient is released over a period of atleast about 30 hours. In some embodiments, 60% and about 100% of theactive pharmaceutical ingredient is released over a period of at leastabout 30 hours. In some embodiments, between about 65% and about 100% ofthe active pharmaceutical ingredient is released over a period of atleast about 36 hours. In some embodiments, 80% and about 100% of theactive pharmaceutical ingredient is released over a period of at leastabout 36 hours. In some embodiments, between about 60% and about 100% ofthe active pharmaceutical ingredient is released over a period of atleast about 48 hours. In some embodiments, 80% and about 100% of theactive pharmaceutical ingredient is released over a period of at leastabout 48 hours. In some embodiments, between about 60% and about 100% ofthe active pharmaceutical ingredient is released over a period of atleast about 60 hours. In some embodiments, 80% and about 100% of theactive pharmaceutical ingredient is released over a period of at leastabout 60 hours.

In some embodiments, substrate 22 includes a hydrophilic component, suchas, for example, PEG and a crosslinking agent that is applied tosubstrate 22. The hydrophilic component and the crosslinking agent forma hydrogel that absorbs blood and reduces bleeding when in contact withblood or tissue fluid. In some embodiments, the hydrophilic componentand the crosslinking agent are sprayed directly onto substrate 22. Insome embodiments, the hydrophilic component and the crosslinking agentare provided in a polymer, such as, for example, one or more of thepolymers discussed herein, and the polymer is applied directly ontosubstrate 22. In some embodiments, the hydrophilic component and thecrosslinking agent are provided in a patch, such as, for example, theVeriset™ hemostatic patch available from Medtronic, Inc., and the patchis applied directly onto substrate 22. In some embodiments, the patchcomprises a plurality of layers. For example, a first layer of the patchcan include a hemostatic agent, such as, for example, oxidizedregenerated cellulose and/or one or more of the hemostatic agentsdiscussed herein. A second layer of the patch can include a crosslinkingagent, such as, for example, trilysine and/or one or more of thecrosslinking agents discussed herein. A third layer of the patch caninclude a hydrophilic agent, such as, for example, PEG and/or one ormore of the hydrophilic agents discussed herein. The second layer of thepatch is positioned between the first and third layers of the patch.

In some embodiments, the hydrophilic component comprises thermogellinghydrogels, PEG-PLGA copolymers, PEG-Poly(N-isopropyl acrylamide),Pluronic (PEO-PPO-PEO triblock), PEG-PCL polymers, PEG-based amphiphiliccopolymers modified by anionic weak polyelectrolytes, (such aspolyacrylic acid, polyglutamic acid) and polymers containing sulfonamidegroups), PEG-based amphiphilic copolymers modified by cationic weakpolyelectrolytes (such as poly (2-vinyl pyridine), Poly(beta-aminoesters), poly (2-(dimethylamino)ethyl methacrylate), multiarm PEGderivatives such as those available from JenKem technology, multiarmedblock and graft PLA copolymers with PEG, PEG with stereo complexedpoly(lactide), acrylated polymers (such as Polyvinylalcohol, dextran,Polyvinylpyrollidone, chitosan, alginate, hyaluronic acid), andcombinations thereof. In some embodiments, the crosslinking agentcomprises one or more agents that induce polymerization of vinyl groupsusing various initiators, light or redox reactions, or by reactions suchas Schiff base formation, Michael type additions, peptide ligation,clock chemistry of functional groups present; one or more agents thatinduce crosslinking by enzymatic reaction (transglutaminase mediatedreaction between carboxamide and amine on proteins),stereo-complexation, metal chelation (alginates using calciumCal2),thermogelation, self-assembly (formation of super helices from proteinchains) inclusion complexation (using cyclodextrin); and combinationsthereof.

In some embodiments, implantable medical device 24 is not part of kit20. In some embodiments, implantable medical device 24 is part of kit20, as shown in FIG. 1. In embodiments wherein implantable medicaldevice 24 is part of kit 20, it is envisioned that implantable medicaldevice 24 may be packaged separately from substrate 22 or together withsubstrate 22. For example, in some embodiments, implantable medicaldevice 24 may be packaged in a first container, such as, for example,package 26 a shown in FIG. 5 and substrate 22 may be packaged in asecond container, such as, for example, package 26 b. Alternatively,implantable medical device 24 and substrate 22 may be packaged togetherin the same container, such as, for example, package 26 a or package 26b. In some embodiments, at least one of package 26 a and package 26 b issterilized.

In some embodiments, implantable medical device 24 is selected from thegroup consisting of neurostimulators, vascular devices such as grafts(e.g., abdominal aortic aneurysm grafts, etc.), stents, catheters(including arterial, intravenous, blood pressure, stent graft, etc.),valves (e.g., polymeric or carbon mechanical valves), embolic protectionfilters (including distal protection devices), vena cava filters,aneurysm exclusion devices, artificial hearts, cardiac jackets, andheart assist devices (including left ventricle assist devices),implantable defibrillators, subcutaneous implantable defibrillators,implantable monitors, for example, implantable cardiac monitors,electrostimulation devices and leads (including pacemakers, leadadapters and lead connectors), implanted medical device power supplies,peripheral cardiovascular devices, atrial septal defect closures, leftatrial appendage filters, valve annuloplasty devices, mitral valverepair devices, vascular intervention devices, ventricular assist pumps,and vascular access devices (including parenteral feeding catheters,vascular access ports, central venous access catheters).

In some embodiments, implantable medical device 24 is selected from thegroup consisting of sutures of all types, anastomosis devices (includinganastomotic closures), suture anchors, hemostatic barriers, screws,plates, clips, vascular implants, tissue scaffolds, cerebro-spinal fluidshunts, shunts for hydrocephalus, drainage tubes, catheters includingthoracic cavity suction drainage catheters, abscess drainage catheters,biliary drainage products, and implantable pumps. In some embodiments,implantable medical device 24 is selected from the group consisting oforthopedic devices such as joint implants, acetabular cups, patellarbuttons, bone repair/augmentation devices, spinal devices (e.g.,vertebral disks and the like), bone pins, cartilage repair devices, andartificial tendons. In some embodiments, implantable medical device 24is selected from the group consisting of dental devices such as dentalimplants and dental fracture repair devices. In some embodiments,implantable medical device 24 is selected from the group consisting ofdrug delivery devices such as drug delivery pumps, implanted druginfusion tubes, drug infusion catheters, and intravitreal drug deliverydevices. In some embodiments, implantable medical device 24 is selectedfrom the group consisting of ophthalmic devices such as scleral bucklesand sponges, glaucoma drain shunts and intraocular lenses.

In some embodiments, implantable medical device 24 is selected from thegroup consisting of urological devices such as penile devices (e.g.,impotence implants), sphincter, urethral, prostate, and bladder devices(e.g., incontinence devices, benign prostate hyperplasia managementdevices, prostate cancer implants, etc.), urinary catheters includingindwelling (“Foley”) and non-indwelling urinary catheters, and renaldevices. In some embodiments, implantable medical device 24 is selectedfrom the group consisting of synthetic prostheses such as breastprostheses and artificial organs (e.g., pancreas, liver, lungs, heart,etc.). In some embodiments, implantable medical device 24 is selectedfrom the group consisting of respiratory devices including lungcatheters. In some embodiments, implantable medical device 24 isselected from the group consisting of neurological devices such asneurostimulators, neurological catheters, neurovascular ballooncatheters, neuro-aneurysm treatment coils, and neuropatches, splints,ear wicks, ear drainage tubes, tympanostomy vent tubes, otologicalstrips, laryngectomy tubes, esophageal tubes, esophageal stents,laryngeal stents, salivary bypass tubes, and tracheostomy tubes. In someembodiments, implantable medical device 24 is selected from the groupconsisting of oncological implants and pain management implants.

Kit 20 includes an agent, such as, for example, a hemostatic agent 28.In some embodiments, hemostatic agent 28 is packaged in a container,such as, for example, a vial 30, as shown in FIG. 1. Hemostatic agent 28is packaged separately from substrate 22 that is coated with the polymerincluding the active pharmaceutical agent. In some embodiments,hemostatic agent 28 is water soluble and is insoluble in organicsolvents. In some embodiments, hemostatic agent 28 is water soluble andis denatured by organic solvents. In some embodiments, a solutioncomprising hemostatic agent 28 and an organic solvent is stored withinvial 30. In some embodiments, a solution comprising hemostatic agent 28and PEG is stored within vial 30. In some embodiments, a solutioncomprising hemostatic agent 28 is stored within vial 30 and kit 20includes a vial similar to vial 30 containing PEG. This allowshemostatic agent 28 and PEG to be administered to a target area togethersuch that the PEG forms a gel when it is introduced into the patient toprevent migration of hemostatic agent 28 within the patient, asdiscussed herein. In some embodiments, a powder comprising hemostaticagent 28 is stored within vial 30 and kit 20 includes a vial similar tovial 30 containing an organic solvent such that the organic solvent canbe added to vial 30 at the time of surgery to reconstitute hemostaticagent 28.

In some embodiments, implantable medical device 24 may be packaged in afirst container, such as, for example, package 26 a shown in FIG. 5,substrate 22 may be packaged in a second container, such as, forexample, package 26 b, and vial 30 may be packaged in a third container,such as, for example, package 26 c. In some embodiments, implantablemedical device 24 may be packaged in a first container, such as, forexample, package 26 a and substrate 22 and vial 30 may be packaged in asecond container, such as, for example, package 26 b or package 26 c. Insome embodiments, implantable medical device 24 and substrate 22 may bepackaged in a first container, such as, for example, package 26 a andvial 30 may be packaged in a second container, such as, for example,package 26 b or package 26 c. In some embodiments, vial 30 and substrate22 may be packaged in a first container, such as, for example, package26 a and implantable medical device 24 may be packaged in a secondcontainer, such as, for example, package 26 b or package 26 c. In someembodiments, vial 30, implantable medical device 24, substrate 22 may bepackaged together in the same container, such as, for example, package26 a, package 26 b, or package 26 c. In some embodiments, at least oneof package 26 a, package 26 b and package 26 is sterilized.

Hemostatic agent 28 can include one more hemostatic agent, such as, forexample, epinephrine, tranexamic acid, chitosan and oxidized regeneratedcellulose. In some embodiments, hemostatic agent 28 can include one ormore of Spongostan, Surgifoam®, Avitene, thrombin and Ostene® inaddition to or in place of the hemostatic agents discussed above. Insome embodiments, hemostatic agent 28 can include one or more ofprotamine, norepinephrine, desmopressin, lysine analogs, collagen,gelatin, polysaccharide spheres, mineral zeolite, bovine thrombin,pooled human thrombin, recombinant thrombin, gelatin and thrombin,collagen and thrombin, cyanacrylate, fibrin glue, polyethylene glycol,and glutaraldehyde in addition to or in place of the hemostatic agentsdiscussed above. In some embodiments, the lysine analog is tranexamicacid and has the formula:

In some embodiments, hemostatic agent 28 includes one or morepharmacologic hemostatic agent since pharmacologic hemostatic agentshave been found to be desirable over mechanical hemostats for a varietyof reasons. Ethnographic research has showed that physicians desire ahemostat that can provide an extended elution profile to reduce bleedingevents for up to 7 days post operatively. Furthermore, there is apossible effect on handling and/or allergic reactions if mechanicalhemostats, such as, for example, oxidized regenerated cellulose orchitosan were used.

In some embodiments, tranexamic acid is preferred for use as hemostaticagent 28. Tranexamic acid is a synthetic analog of the amino acid lysinewith a molecular weight of 157 g/mol. Tranexamic acid is anantifibrinolytic agent that acts by binding to plasminogen and blockingthe interaction of plasminogen with fibrin, therefore preventing thedissolution of a fibrin clot. In the presence of a wound, fibrinolysisoccurs naturally when alysine residue such as tissue plasminogenactivator (tPA), binds to plasmin causing the clot to lyse (or break).Tranexamic acid blocks tPA and keeps the clot from breaking, thuspreventing unwanted bleeding.

Prior to a damaged endothelium, tPA is inhibited in the blood byplasminogen activator inhibitor/type 1 (PAI-1). Once damage occurs, thetPA is released slowly into the blood, activating fibrinolysis.Excessive fibrinolysis results in a condition called hvperfibrinolysis,which requires intervention such as fibrinogen, plasma, transfusion orantifibrinolytic therapy, such as tranexamic acid.

Tranexamic acid has been used for over 40 years to reduce bleedingcomplications. Tranexamic acid is most commonly given systemically atdoses of 10 mg/kg followed by infusion of 10 mg/kg/h. Since 2007,tranexamic acid has received widespread approval and clinical use as ahemostatic agent. Knowing that surgical trauma causes fibrinolysis inthe area of the surgical wound itself, topical antifibrinolytic therapyis becoming more common to obtain and maintain hemostasis. Clinicaltrials with topical tranexamic acid use exist for cardiac surgery, CIEDprocedures, orthopedic surgery, spinal surgery, dental extraction andepistaxis, and breast mammoplasty.

To evaluate the efficacy of tranexamic acid, a non-GLP acute porcinestudy was conducted. Doses of 1 mg to 200 mg of tranexamic acid wereused in an in vitro whole blood coagulation test, a hepatic biopsy test,and a subcutaneous ICD surgical procedure.

The in vitro whole blood coagulation test showed no activity fortranexamic acid up to 10 mg/ml. The maximum tranexamic acidconcentration, 200 mg/5 ml, was a slightly higher dose than that usedclinically in a CIED pocket if 50 cc is the assumed blood volume ofinterest. Coagulation time was doubled with this higher dose.

The hepatic biopsy test had a volume of 0.016 ml when the biopsy holewas filled with blood. The minimum tranexamic acid dose evaluated was2.5 mg, which is equivalent to 156 mg/ml. This concentration preventsblood from clotting quickly and these biopsies continued to bleed pastthe endpoint of 10 minutes. This phenomenon is likely due to themultiple bonding sites available to tranexamic acid in whole blood, andthe fact that a biopsy does not induce fibrinolysis.

The subcutaneous surgical site test was conducted with an elevated ACTusing heparin to induce hematoma. Surgical trauma similar to that of aCIEO implant was incurred in each pocket, but some subcutaneous pocketsincurred more trauma than others due to anatomical location. The primaryoutput monitored was accumulated blood as measured by pre-weighed gauze3-hours post-operatively. With only one animal, and two pockets pertreatment, the sample size was too low to show any significance betweenICD only, ICD+polymer, and ICD+polymer+tranexamic acid.

The non-GLP acute porcine study showed that in the dose range evaluated,tranexamic acid has a two-fold increase on clotting time and no effecton reducing bleeding on the hepatic biopsies. In the heparinized ICDpocket procedure, 3.5-22.8 grams of blood accumulated in a 3-hour periodof time regardless of treatment. It appears that subcutaneous pockets inan anticoagulated porcine model would be a translatable model forevaluating efficacy of tranexamic acid because it has a relevant volumeof accumulated blood and surgical trauma similar to that of a CIEDprocedure.

Based upon the non-GLP acute porcine study, tranexamic acidconcentrations of 3.00 mg/L to 30 mg/L are effective in preventingfibrinolysis. As such, in some embodiments, hemostatic agent 28 istranexamic acid and is provided in concentrations of about 3.00 mg/L toabout 30 mg/L. However, it has been found that one tenth of the dosesused in the non-GLP acute porcine study can be effective in reversingfibrinolysis. As such, in some embodiments, hemostatic agent 28 istranexamic acid and is provided in concentrations of about 0.30 mg/L toabout 3.0 mg/L for intravenous applications. In some embodiments,tranexamic acid is provided in concentrations of about 3.78 mg/L toabout 30 mg/L for topical applications as well. However, in someembodiments, however, higher doses of tranexamic acid are used fortopical applications to account for tranexamic acid being widelydistributed throughout the extracellular and intracellular compartmentswhen given preoperatively. Indeed, it has been found that tranexamicacid reaches plasma concentrations in 5-15 minutes. As such, in someembodiments, tranexamic acid is provided in doses of about 1.5 mg toabout 150 mg. In some embodiments, hemostatic agent 28 includes amixture or combination of the hemostatic agents discussed herein.

In some embodiments, hemostatic agent 28 includes one or more naturallyoccurring inhibitors of fibrinolysis. In some embodiments, theinhibitors of fibrinolysis are selected from agents that inhibit theactivation of plasminogen and agents that act against plasmin directlyPlasmin inhibitors include, for example, α₁-Antitrypsin (mol. wt. 54000,mean concentration 290 (mg/100 ml), α₂-Macroglobulin (mol. wt. 820000,mean concentration 260 (mg/100 ml), Inter-α₁-inhibitor (mol. wt. 160000,mean concentration 50 (mg/100 ml), C1-inactivator (mol. wt. 104000, meanconcentration 24 (mg/100 ml), and Antithrombin II (mol. wt. 65000, meanconcentration 40 (mg/100 ml). In some embodiments, hemostatic agent 28includes one or more inhibitors from blood platelets. In someembodiments, hemostatic agent 28 includes one or more endogenousinhibitors of fibrinolysis from other body fluids and tissues, such as,for example, urokinase inhibitors. In some embodiments, hemostatic agent28 includes one or more inhibitors of proteolytic enzymes from animals(non-humans), such as, for example, human parasites and non-humanparasites. In some embodiments, hemostatic agent 28 includes one or moreinhibitors from bovine organs, bovine colostrum, guinea pig seminalvesicles, dog submandibular glands, leeches and/or snails. In someembodiments, hemostatic agent 28 includes Aprotinin, Iniprol, Trasyloland/or Contrykal. In some embodiments, hemostatic agent 28 includes oneor more protease inhibitors from plants, such as, for example, trypsininhibitors from soybeans, potatoes, peanuts and/or lima beans. In someembodiments, hemostatic agent 28 includes one or more agents discussedin Markward F. Naturally occurring inhibitors of fibrinolysis, In:Markwardt F, ed. Fibrinolytics and anti-fibrinolytics (Handbook derexperimentellen Pharmakologie, vow 46), Berlin: Springer, 1978: 487-509,which is expressly incorporated by reference herein, in its entirety.

In some embodiments, hemostatic agent 28 includes one or more syntheticinhibitors of fibrinolysis, such as, for example, ε-Aminocaproic acid(EACA), p-aminomethylbenzoic acid (PAMBA),trans-4-aminomethylcyclohexanecarboxylic acid-(1) (AMCA), 4-Aminobenzoicacid, 4-Aminocyclohexanecarboxylic acid-(1),cis/trans-4-Aminomethylcyclohexanecarboxylic acid-(1) (AMCA),4-Aminoethylbenzoic acid, 4-Aminoethylcyclohexanecarboxylic acid-(1),4-Aminophenylacetic acid, 4-aminocyclohexane-acetic acid,4-Aminomethylphenyl acetic acid and/or 4-Aminomethylcyclohexane aceticacid. In some embodiments, hemostatic agent 28 includes derivatives ofPAMBA, such as, for example, PAMBA methyl ester, PAMBA ethyl ester,PAMBA amide, 4-Aminomethylbenzene sulphonic acid, benzylamine,N-Acetyl-PAMBA, N-Dimethyl-PAMBA, Carbamyl-PAMBA,4-Guanidinomethyl-benzoic acid, 4-Amidinobenzoic acid,4-Guanidinobenzoic acid, 4-Toluic acid, 4-(α-Amino)-ethylbenzoic acid,4-(α-Amino)-propylbenzoic acid, 2-Hydroxy-PAMBA, 3-Nitro-PAMBA and/or3-Aminomethylbenzoic acid. In some embodiments, hemostatic agent 28includes derivatives of benzylamine. In some embodiments, hemostaticagent 28 includes derivatives of lysine and/or other basic amino acids.In some embodiments, hemostatic agent 28 includes quaternary products ofEACA, quaternary products of other ε-aminocarboxylic acids, primaryalphatic amines, lactams of carboxylic acids and/or lactones ofcarboxylic acids. In some embodiments, hemostatic agent 28 includes oneor more agents discussed in Markward F. Synthetic inhibitors offibrinolysis, In: Markwardt F, ed. Fibrinolytics and anti-fibrinolytics(Handbuch der experimentellen Pharmakologie, vol 46), Berlin: Springer,1978:511-77, which is expressly incorporated by reference herein, in itsentirety. It is envisioned that hemostatic agent 28 can include one ormore of any of the hemostatic agents discussed herein.

Hemostatic agent 28 is configured to be delivered to a target area toreduce or prevent bleeding within a patient, such as, for example,bleeding caused by a surgical procedure. By providing substrate 22 andhemostatic agent 28 separately, kit 20 allows hemostatic agent 28 to beadministered before substrate 22 is implanted, at the same time thatsubstrate 22 is implanted, or after substrate 22 is implanted. Providingsubstrate 22 and hemostatic agent 28 separately eliminates the need todevelop a formulation of hemostatic agent in the polymer that coatssubstrate 22. That is, the type of hemostatic agent and the amount ofhemostatic agent can be selected using hemostatic agent 28, rather thanincorporating a hemostatic agent into substrate 22 and/or the polymerthat coats substrate 22. Therefore, in some embodiments, kit 20 includesa plurality of containers similar to vial 30 wherein each containerincludes a different hemostatic agent, such as, for example, one or moreof the hemostatic agents discussed herein. This allows a medicalpractitioner to select the hemostatic agent from kit 20 that is bestsuited for a particular application. In some embodiments, kit 20includes a plurality of containers similar to vial 30 wherein eachcontainer includes the same hemostatic agent, such as, for example, oneor more of the hemostatic agents discussed herein, wherein eachcontainer has a different amount or concentration of the hemostaticagent.

In some embodiments, kit 20 includes an absorbable substrate 32. In someembodiments, kit 20 includes a plurality of substrates 32. In someembodiments, substrates 32 are packaged in a container, such as, forexample, a dispenser 34, as shown in FIG. 1. In some embodiments,dispenser 34 is configured to dispense one substrate 32 at a time.Substrates 32 are configured to absorb hemostatic agent 28. That is,substrates 32 can be soaked in a selected amount or selectedconcentration of hemostatic agent 28 until substrates 32 absorbhemostatic agent 28. In some embodiments, once at least one ofsubstrates 32 is at least partially absorbs hemostatic agent 28, atleast one of substrates 32 can be applied to substrate 22 such to allowthe polymer that coats substrate 22 and/or substrate 22 itself to absorbhemostatic agent 28. Substrate 22 is implanted in the patient aftersubstrate 22 and/or the polymer that coats substrate 22 absorbshemostatic agent to administer hemostatic agent 28 to a target areawithin the patient. In some embodiments, substrate 32 is removed fromsubstrate 22 before substrate 22 is implanted within the patient. Insome embodiments, substrate 32 is coupled to substrate 22 when substrate22 is implanted within the patient. In some embodiments, substrate 32 iscoupled to substrate 22 after substrate 22 is implanted within thepatient. That is, substrate 32 is implanted in the patient aftersubstrate 22 is implanted.

In some embodiments, substrate 32 comprises a planar single layer sheet.In some embodiments, substrate 32 comprises a sheet that includesoxidized regenerated cellulose Oxidized cellulose, Cellulose derivativeslike carboxymethyl, hydroxypropyl, hydroxyethyl, Hyaluronic acid, Plantbased polysaccharides, Gelatin, collagen, Chitosan, PVP, Polyacrylicacid, Copolymers of PEG and hydroxyacid polymers—such as polymerscomprising lactic acid, glycolic acid, e-caprolactone, dioxanone,trimethylene carbonate, hydroxy alkanoates like hydroxybutyrate,Copolymers of PEG with tyrosine derived diphenols, includingpolyarylates, polycarbonates, polyiminocarbonates, polyurethanes,Extracellular matrices-plant, animal or human derived. In someembodiments, substrate 32 comprises paper pulps, wherein the pulps areselected from the group consisting of softwood, hardwood, fiber crops,and mineral fibers. In some embodiments, substrate 32 comprises a sheetof filter paper. In some embodiments, the filter paper is crêped toimprove porosity. In some embodiments, the filter paper is qualitativefilter paper. The qualitative filter paper may be selected from thegroup consisting of grade 1 qualitative filter paper, grade 2qualitative filter paper, grade 3 qualitative filter paper, grade 4qualitative filter paper, and grade 602h qualitative filter paper. Insome embodiments, the filter paper is quantitative filter paper.

In some embodiments, kit 20 includes a second hemostatic agent, such as,for example, a hemostatic agent 36. In some embodiments, hemostaticagent 36 is packaged in a container, such as, for example, a vial 38, asshown in FIG. 1. In some embodiments, hemostatic agent 36 is watersoluble and is insoluble in organic solvents. In some embodiments,hemostatic agent 36 is water soluble and is denatured by organicsolvents. Hemostatic agent 36 may include one or more of the hemostaticagents discussed herein, such as, for example, one or more of thehemostatic agents discussed herein that define hemostatic agent 28. Insome embodiments, hemostatic agent 36 is different than hemostatic agent28. In some embodiments, hemostatic agent 36 is the same as hemostaticagent 28. In some embodiments, a solution comprising hemostatic agent 36and an organic solvent is stored within vial 38. In some embodiments, apowder comprising hemostatic agent 36 is stored within vial 38 and kit20 includes a vial similar to vial 38 containing an organic solvent suchthat the organic solvent can be added to vial 38 at the time of surgeryto reconstitute hemostatic agent 36.

In some embodiments, hemostatic agent 36 is configured to polymerize orgel upon introduction into a human body. In some embodiments, hemostaticagent 36 is configured to polymerize or gel by chelation with metalions, chemical reactions, or light. In some embodiments, hemostaticagent 36 comprises PEG. In some embodiments, hemostatic agent 36consists of PEG. Hemostatic agent 28 and hemostatic agent 36 to beadministered to a target are together such that the PEG forms a gel whenit is introduced into the patient to prevent migration of hemostaticagent 28 within the patient, as discussed herein. In some embodiments,the PEG is selected from the group consisting of PEG-200, PEG-300,PEG-400, PEG-600, PEG-1000, PEG-1450, PEG-3350, PEG-4000, PEG-6000,PEG-8000, PEG-20000, PEG-400-succinate, PEG-600-succinate, andPEG-1000-succinate. In some embodiments, the PEG is a blend of differentPEGs, such as, for example, a blend of two or more of the PEGs discussedherein. In some embodiments, a powder comprising hemostatic agent 36 isstored within vial 38 and kit 20 includes a vial similar to vial 38containing an organic solvent such that the organic solvent can be addedto vial 38 at the time of surgery to reconstitute hemostatic agent 26.

In some embodiments, kit 20 may include one or a plurality of meshsubstrates, such as, for example, substrates 22. It is contemplated thateach of the mesh substrates can have a different configuration. In someembodiments, the mesh substrates can include different activepharmaceutical ingredients and/or different amounts of activepharmaceutical ingredients. In some embodiments, the mesh substrates caninclude different sizes and/or shapes, to accommodate different sizeimplantable medical devices, for example. In some embodiments, kit 20includes one or a plurality of medical devices, such as, for example,the implantable medical devices discussed herein. In some embodiments,kit 20 includes instructions for use.

In operation and use, substrate 22 is configured to be implanted at atarget site in the body of a patient such that substrate 22 covers atleast a portion of one or more implantable medical device 24, which isimplanted at the target site. In some embodiments, substrate 22 iscoupled to implantable medical device 24 before implantable medicaldevice 24 is implanted at the target site. That is, implantable medicaldevice 24 is implanted with substrate 22 coupled to implantable medicaldevice 24 to implant implantable medical device 24 and substrate 22simultaneously.

In some embodiments wherein hemostatic agent 28 is in a solution,substrate 22 may be soaked in hemostatic agent 28 before implantablemedical device 24 and substrate 22 are implanted, such that the polymerthat coats substrate 22 and/or substrate 22 itself absorb hemostaticagent 28. Implantable medical device 24 is then implanted with substrate22 coupled to implantable medical device 24.

In some embodiments wherein kit 20 includes substrate(s) 32, at leastone substrate 32 may be soaked with hemostatic agent 28 such thatsubstrate(s) 32 absorb hemostatic agent 28. Substrate(s) 32 is/are thendraped over substrate 22 such that the polymer that coats substrate 22and/or substrate 22 itself absorb hemostatic agent 28 from substrate(s)32. Implantable medical device 24 is then implanted with substrate 22coupled to implantable medical device 24. In some embodiments,substrate(s) 32 is/are removed from substrate 22 before substrate 22 iscoupled to implantable medical device 24. In some embodiments,substrate(s) 32 is/are coupled to substrate 22 when substrate 22 iscoupled to implantable medical device 24. That is, substrate(s) 32is/are implanted with substrate 22 such that substrate(s) 32 remainwithin the patient after the surgical procedure is complete.

In some embodiments wherein hemostatic agent 28 is in a solution,hemostatic agent may be administered to the target site before, duringor after implantable medical device 24 and substrate 22 are implanted.For example, hemostatic agent 28 may be delivered to the target locationbefore implantable medical device 24 is implanted with substrate 22coupled to implantable medical device 24. Alternatively, hemostaticagent 28 may be delivered to the target location at the same timeimplantable medical device 24 is implanted with substrate 22 coupled toimplantable medical device 24. Alternatively, hemostatic agent 28 may bedelivered to the target location after implantable medical device 24 isimplanted with substrate 22 coupled to implantable medical device 24. Insome embodiments, hemostatic agent 28 is injected into the patient. Insome embodiments, hemostatic agent 28 is injected into the patient suchthat hemostatic agent 28 comes into contact with substrate 22 and/orimplantable medical device 24.

In some embodiments wherein kit 20 includes hemostatic agent 36,substrate 22 may be soaked in hemostatic agent 36 before implantablemedical device 24 and substrate 22 are implanted, such that the polymerthat coats substrate 22 and/or substrate 22 itself absorb hemostaticagent 36. Implantable medical device 24 is then implanted with substrate22 coupled to implantable medical device 24. When hemostatic agent 36 isintroduced into the patient, hemostatic agent 36 will cross-link to forma gel to prevent hemostatic agent 28 from migrating from the target areaand/or reduce the amount that hemostatic agent 28 migrates from thetarget area. In some embodiments, substrate 22 may also be soaked inhemostatic agent 28 before implantable medical device 24 and substrate22 are implanted, such that the polymer that coats substrate 22 and/orsubstrate 22 itself absorb hemostatic agent 28. In some embodiments,hemostatic agent 28 is added or otherwise combined with hemostatic agent36 and substrate 22 is soaked in hemostatic agents 28, 36 beforeimplantable medical device 24 and substrate 22 are implanted, such thatthe polymer that coats substrate 22 and/or substrate 22 itself absorbshemostatic agents 28, 36. Implantable medical device 24 is thenimplanted with substrate 22 coupled to implantable medical device 24. Insome embodiments, hemostatic agent 36 includes a cross-linking agent,such as, for example, one or more of the cross-linking agents discussedherein.

In some embodiments wherein kit 20 includes hemostatic agent 36,hemostatic agent 28 is added or otherwise combined with hemostatic agent36. Implantable medical device 24 is implanted with substrate 22 coupledto implantable medical device 24. Hemostatic agents 28, 36 are injectedtogether to deliver hemostatic agents 28, 36 to the target area. In someembodiments, hemostatic agents 28, 36 are injected before implantablemedical device 24 is implanted with substrate 22 coupled to implantablemedical device 24. In some embodiments, hemostatic agents 28, 36 areinjected after implantable medical device 24 is implanted with substrate22 coupled to implantable medical device 24. In some embodiments,hemostatic agents 28, 36 are injected at the same time implantablemedical device 24 is implanted with substrate 22 coupled to implantablemedical device 24.

In some embodiments wherein kit 20 includes hemostatic agent 36,hemostatic agents 28, 36 are each injected into the patient to deliverhemostatic agents 28, 36 to the target area. In some embodiments,hemostatic agent 28 is injected into the patient before hemostatic agent36 is injected into the patient. In some embodiments, hemostatic agent28 is injected into the patient after hemostatic agent 36 is injectedinto the patient. In some embodiments, hemostatic agents 28, 36 areinjected into the patient simultaneously using different deliverydevices, such as, for example, different syringes. In some embodiments,at least one of hemostatic agents 28, 36 is injected into the patientbefore implantable medical device 24 is implanted with substrate 22coupled to implantable medical device 24. In some embodiments, at leastone of hemostatic agents 28, 36 is injected into the patient afterimplantable medical device 24 is implanted with substrate 22 coupled toimplantable medical device 24. In some embodiments, at least one ofhemostatic agents 28, 36 is injected into the patient at the same timeimplantable medical device 24 is implanted with substrate 22 coupled toimplantable medical device 24.

In some embodiments wherein kit 20 includes substrate(s) 32 andhemostatic agent 36, substrate(s) 32 may be soaked in hemostatic agent36 before implantable medical device 24 and substrate 22 are implanted.Substrate(s) 32 is/are then draped over substrate 22 such that thepolymer that coats substrate 22 and/or substrate 22 itself absorbhemostatic agent 36. Implantable medical device 24 is then implantedwith substrate 22 coupled to implantable medical device 24. Whenhemostatic agent 36 is introduced into the patient, hemostatic agent 36will cross-link to form a gel to prevent hemostatic agent 28 frommigrating from the target area and/or reduce the amount that hemostaticagent 28 migrates from the target area. In some embodiments,substrate(s) 32 may also be soaked in hemostatic agent 28 beforeimplantable medical device 24 and substrate 22 are implanted.Substrate(s) 32 is/are then draped over substrate 22 such that thepolymer that coats substrate 22 and/or substrate 22 itself absorbhemostatic agent 28. In some embodiments, hemostatic agent 28 is addedor otherwise combined with hemostatic agent 36 and substrate(s) 32is/are soaked in hemostatic agents 28, 36 before implantable medicaldevice 24 and substrate 22 are implanted, such that the polymer thatcoats substrate 22 and/or substrate 22 itself absorb hemostatic agents28, 36. Implantable medical device 24 is then implanted with substrate22 coupled to implantable medical device 24. In some embodiments,substrate(s) 32 is/are removed from substrate 22 before substrate 22 iscoupled to implantable medical device 24. In some embodiments,substrate(s) 32 is/are coupled to substrate 22 when substrate 22 iscoupled to implantable medical device 24. That is, substrate(s) 32is/are implanted with substrate 22 such that substrate(s) 32 remainwithin the patient after the surgical procedure is complete.

In some embodiments, substrate 22 is coupled to implantable medicaldevice 24 after implantable medical device 24 is implanted at the targetsite. That is, implantable medical device 24 is implanted by itself.Substrate 22 is then coupled to implantable medical device 24.

In some embodiments wherein hemostatic agent 28 is in a solution,substrate 22 may be soaked in hemostatic agent 28 before substrate 22 iscoupled to implantable medical device, such that the polymer that coatssubstrate 22 and/or substrate 22 itself absorb hemostatic agent 28.Substrate 22 is then coupled to implantable medical device 24, which wasimplanted previously.

In some embodiments wherein kit 20 includes substrate(s) 32, at leastone substrate 32 may be soaked with hemostatic agent 28 such thatsubstrate(s) 32 absorb hemostatic agent 28. Substrate(s) 32 is/are thendraped over substrate 22 such that the polymer that coats substrate 22and/or substrate 22 itself absorb hemostatic agent 28 from substrate(s)32. Substrate 22 is then coupled to implantable medical device 24, whichwas implanted previously. In some embodiments, substrate(s) 32 is/areremoved from substrate 22 before substrate 22 is coupled to implantablemedical device 24. In some embodiments, substrate(s) 32 is/are coupledto substrate 22 when substrate 22 is coupled to implantable medicaldevice 24. That is, substrate(s) 32 is/are implanted with substrate 22such that substrate(s) 32 remain within the patient after the surgicalprocedure is complete. In embodiments wherein hemostatic agent 28 and/orhemostatic agent 36 is/are injected into the patient, at least one ofhemostatic agents 28, 36 may be provided as a solution in kit 20. Inembodiments wherein hemostatic agent 28 and/or hemostatic agent 36is/are injected into the patient, at least one of hemostatic agents 28,36 may be provided as powder and kit 20 can include a liquid component,such as, for example, a non-organic solvent that may be added tohemostatic agent 28 and/or hemostatic agent 36 to reconstitutehemostatic agent 28 and/or hemostatic agent 36.

In some embodiments wherein hemostatic agent 28 is in a solution,hemostatic agent 28 may be administered to the target site afterimplantable medical device 24 and substrate 22 are implanted. That is,substrate 22 is coupled to implantable medical device 24 afterimplantable medical device 24 is implanted. Hemostatic agent 28 may thenbe delivered to the target site and/or an area adjacent to the targetsite after substrate 22 is coupled to implantable medical device 24. Insome embodiments, hemostatic agent 28 is injected into the patient. Insome embodiments, hemostatic agent 28 is injected into the patient suchthat hemostatic agent 28 comes into contact with substrate 22 and/orimplantable medical device 24.

In some embodiments wherein kit 20 includes hemostatic agent 36,substrate 22 may be soaked in hemostatic agent 36 before implantablemedical device 24 and substrate 22 are implanted, such that the polymerthat coats substrate 22 and/or substrate 22 itself absorb hemostaticagent 36. Implantable medical device 24 is then implanted. Substrate 22is then implanted such that substrate 22 covers at least a portion ofimplantable medical device 24, which was implanted before substrate 22was implanted. When hemostatic agent 36 is introduced into the patient,hemostatic agent 36 will cross-link to form a gel to prevent hemostaticagent 28 from migrating from the target area and/or reduce the amountthat hemostatic agent 28 migrates from the target area. In someembodiments, substrate 22 may also be soaked in hemostatic agent 28before implantable medical device 24 is implanted, such that the polymerthat coats substrate 22 and/or substrate 22 itself absorb hemostaticagent 28. In some embodiments, hemostatic agent 28 is added or otherwisecombined with hemostatic agent 36 and substrate 22 is soaked inhemostatic agents 28, 36 before substrate 22 is implanted, such that thepolymer that coats substrate 22 and/or substrate 22 itself absorbhemostatic agents 28, 36. Substrate 22 is then implanted such thatsubstrate 22 covers at least a portion of implantable medical device 24,which was implanted before substrate 22 was implanted.

In some embodiments wherein kit 20 includes hemostatic agent 36,hemostatic agent 28 is added or otherwise combined with hemostatic agent36. Substrate 22 is then implanted such that substrate 22 covers atleast a portion of implantable medical device 24, which was implantedbefore substrate 22 was implanted. Hemostatic agents 28, 36 are injectedtogether to deliver hemostatic agents 28, 36 to the target area. In someembodiments, hemostatic agents 28, 36 are injected into the patientbefore implantable medical device 24 and substrate 22 are implanted. Insome embodiments, hemostatic agents 28, 36 are injected into the patientbefore implantable medical device 24 is implanted into the patient. Insome embodiments, hemostatic agents 28, 36 are injected into the patientafter implantable medical device 24 is implanted, but before substrate22 is implanted. In some embodiments, hemostatic agents 28, 36 areinjected into the patient at the same time implantable medical device 24is implanted. In some embodiments, hemostatic agents 28, 36 are injectedinto the patient at the same time substrate 22 is implanted. In someembodiments, hemostatic agents 28, 36 are injected into the patientafter substrate 22 is implanted.

In some embodiments wherein kit 20 includes hemostatic agent 36,hemostatic agents 28, 36 are each injected into the patient to deliverhemostatic agents 28, 36 to the target area. In some embodiments,hemostatic agent 28 is injected into the patient before hemostatic agent36 is injected into the patient. In some embodiments, hemostatic agent28 is injected into the patient after hemostatic agent 36 is injectedinto the patient. In some embodiments, hemostatic agents 28, 36 areinjected into the patient simultaneously using different deliverydevices, such as, for example, different syringes. In some embodiments,at least one of hemostatic agents 28, 36 is/are injected into thepatient before implantable medical device 24 is implanted into thepatient. In some embodiments, at least one of hemostatic agents 28, 36is/are injected into the patient after implantable medical device 24 isimplanted, but before substrate 22 is implanted. In some embodiments, atleast one of hemostatic agents 28, 36 is/are injected into the patientat the same time implantable medical device 24 is implanted. In someembodiments, at least one of hemostatic agents 28, 36 is/are injectedinto the patient at the same time substrate 22 is implanted. In someembodiments, at least one of hemostatic agents 28, 36 is/are injectedinto the patient after substrate 22 is implanted.

In some embodiments wherein kit 20 includes substrate(s) 32 andhemostatic agent 36, substrate(s) 32 may be soaked in hemostatic agent36 before implantable medical device 24 and/or substrate 22 areimplanted. Substrate(s) 32 is/are then draped over substrate 22 suchthat the polymer that coats substrate 22 and/or substrate 22 itselfabsorb hemostatic agent 36. Substrate 22 is then implanted such thatsubstrate 22 covers at least a portion of implantable medical device 24,which was implanted before substrate 22 was implanted. When hemostaticagent 36 is introduced into the patient, hemostatic agent 36 willcross-link to form a gel to prevent hemostatic agent 28 from migratingfrom the target area and/or reduce the amount that hemostatic agent 28migrates from the target area. In some embodiments, substrate(s) 32 mayalso be soaked in hemostatic agent 28 before substrate 22 is implanted.Substrate(s) 32 is/are then draped over substrate 22 such that thepolymer that coats substrate 22 and/or substrate 22 itself absorbshemostatic agent 28. In some embodiments, hemostatic agent 28 is addedor otherwise combined with hemostatic agent 36 and substrate(s) 32is/are soaked in hemostatic agents 28, 36 before substrate 22 isimplanted, such that the polymer that coats substrate 22 and/orsubstrate 22 itself absorb hemostatic agents 28, 36. Substrate 22 isthen implanted such that substrate 22 covers at least a portion ofimplantable medical device 24, which was implanted before substrate 22was implanted. In some embodiments, substrate(s) 32 is/are removed fromsubstrate 22 before substrate 22 is implanted. In some embodiments,substrate(s) 32 is/are coupled to substrate 22 when substrate 22 isimplanted. That is, substrate(s) 32 is/are implanted with substrate 22such that substrate(s) 32 remain within the patient after the surgicalprocedure is complete.

Hemostatic agent 28 acts to reduce or prevent bleeding within thepatient. In some embodiments, the polymer that coats substrate 22releases an active pharmaceutical agent, such as, for example, one ormore of the active pharmaceutical ingredients discussed herein toprevent, mitigate, or treat a condition within the patient, such as, forexample, a bacterial infection.

In some embodiments, implantable medical device 24 is removed from thepatient after the treatment is completed. In some embodiments, substrate22 remains implanted within the patient after implantable medical device24 is removed. In some embodiments, substrate 22 is removed from thepatient after implantable medical device 24 is removed. To removesubstrate 22, tissue that is ingrown within substrate 22 can be cut orotherwise detached from substrate 22. In some embodiments, a portion ofsubstrate 22 may not be removable from the tissue and will remainimplanted within the patient.

It will be understood that various modifications may be made to theembodiments disclosed herein. Therefore, the above description shouldnot be construed as limiting, but merely as exemplification of thevarious embodiments. Those skilled in the art will envision othermodifications within the scope and spirit of the claims appended hereto.

1-20. (canceled)
 21. A kit comprising: a substrate consisting ofcollagen; a coating that covers at least a portion of the substrate; anda hemostatic agent, wherein the substrate with the coating is disposedin a first package and the hemostatic agent is disposed in a secondpackage that is separate from the first package.
 22. The kit recited inclaim 21, wherein the packages are sterile.
 23. The kit recited in claim21, wherein the coating is a polymer.
 24. The kit recited in claim 21,wherein the coating is a polymer, the polymer having an active agentdispersed therein.
 25. The kit recited in claim 24, wherein the activeagent is selected from the group consisting of antibiotics, antiseptics,and disinfectants.
 26. The kit recited in claim 24, wherein the polymeris a tyrosine-derived polyesteramide.
 27. The kit recited in claim 21,wherein the coating includes a polymer, the polymer having a combinationof minocycline and rifampin dispersed therein.
 28. The kit recited inclaim 27, wherein the polymer is a tyrosine-derived polyesteramide. 29.The kit recited in claim 21, wherein the substrate is a pouch, the pouchdefining a pocket configured for disposal of an implantable medicaldevice.
 30. The kit recited in claim 29, further comprising theimplantable medical device.
 31. The kit recited in claim 30, wherein theimplantable medical device is disposed in a third package that isseparate from the first package and the second package.
 32. The kitrecited in claim 30, wherein the implantable medical device is disposedin the first package.
 33. The kit recited in claim 30, wherein theimplantable medical device is a left ventricle assist device.
 34. Thekit recited in claim 30, wherein the implantable medical device is apacemaker.
 35. The kit recited in claim 21, wherein the hemostatic agentis provided in a solution, the hemostatic agent being selected from thegroup consisting of epinephrine, tranexamic acid, chitosan, oxidizedregenerated cellulose, thrombin, protamine, norepinephrine,desmopressin, lysine analogs, collagen, gelatin, polysaccharide spheres,mineral zeolite, calcium salt, bovine thrombin, pooled human thrombin,recombinant thrombin, gelatin and thrombin, collagen and thrombin,cyanacrylate, fibrin glue, polyethylene glycol, peptide, andglutaraldehyde.
 36. The kit recited in claim 21, wherein: the hemostaticagent is provided in a solution; and the hemostatic agent is tranexamicacid.
 37. The kit recited in claim 21, wherein the substrate is a sheet.38. The kit recited in claim 21, wherein the substrate is a sheet havinga thickness between about 0.0001 inches and about 0.1 inches.
 39. A kitcomprising: an implantable medical device selected from the groupconsisting of cardiac monitors, defibrillators, pacemakers and leftventricle assist devices; a substrate consisting of collagen, thesubstrate comprising a pocket configured for disposal of the implantablemedical device; a tyrosine-derived polyesteramide polymer that covers atleast a portion of the substrate, the polymer having a combination ofminocycline and rifampin dispersed therein; and tranexamic acid, thetranexamic acid being provided in a solution, wherein the substrate withthe polymer and the implantable medical device are disposed in a firstpackage and the hemostatic agent is disposed in a second package that isseparate from the first package.
 40. A kit comprising: an implantablemedical device selected from the group consisting of cardiac monitors,defibrillators, pacemakers and left ventricle assist devices; asubstrate consisting of collagen, the substrate comprising a pocketconfigured for disposal of the implantable medical device; atyrosine-derived polyesteramide polymer that covers at least a portionof the substrate, the polymer having a combination of minocycline andrifampin dispersed therein; and tranexamic acid, the tranexamic acidbeing provided in a solution, wherein the substrate with the polymer isdisposed in a first package, the hemostatic agent is disposed in asecond package that is separate from the first package and theimplantable medical device is disposed in a third package that isseparate from the first package and the second package.